Navigen Pharmaceutical will develop a novel class of protein therapies for treating acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). This work is based on the discovery by our scientific founder, Dean Li, M.D., Ph.D., that there are endogenous signaling pathways that enhance vascular stability and inhibit multiple cytokines and growth factors from inciting vascular leak and edema. Specifically, Dr. Li has found an endothelial specific receptor, Robo4, that is expressed in mature vessels and is upregulated following endothelial injury. Robo4 activated by its cognate ligand, recombinant Slit proteins, reduces agonist induced vascular leak in vitro and in vivo. The central goal of this application is to develop a new class of biologic agents that reduces the noncardiac pulmonary edema of ALI/ARDs. [unreadable] [unreadable] Specific Aim 1: Generate a superior Robo4 agonist by defining the minimum active domain of its endogenous ligand, Slit-2, and creating a Fc fusion protein [unreadable] [unreadable] Specific Aim 2: Investigate whether candidate recombinant Robo4 agonists generated in Aim 1 inhibit vascular leak and reduce acute lung injury in vivo. [unreadable] [unreadable] We will use this Phase I SBIR to generate and compare Robo4 agonists for ease of purification, stability and efficacy. These experiments will lead to a candidate Robo4 agonist that Navigen will advance toward clinical development during a subsequent Phase II for this SBIR. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Navigen Pharmaceutical will develop a novel class of protein therapies for treating acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Both ALI/ARDS are deadly diseases, with no specific treatment and is the cause of death in chemical and biologic warfare and flu pandemics. We will use this Phase I SBIR to generate a candidate biologic that Navigen will advance toward clinical development during a subsequent Phase II for this SBIR. [unreadable] [unreadable] [unreadable]